Bosentan, the mixed ETA-ETB endothelin receptor antagonist, attenuated oxidative stress after experimental myocardial ischemia and reperfusion

Mol Cell Biochem. 2005 Jul;275(1-2):67-74. doi: 10.1007/s11010-005-1999-2.


Endothelin-1 has been shown to be associated with greater myocardial ischemia and reperfusion injury in which oxidative stress plays a key role. The efficacy of bosentan, a mixed ETA-ETB endothelin receptor antagonist, in protecting the myocardium from ischemia-reperfusion injury and oxidative stress was studied in open-chest Wistar rats. Anesthetized adult male rats (175-250 g b wt) underwent sham operation (SHAM group) or were subjected to 40 min of myocardial ischemia (MI) induced by temporary occlusion of the left anterior descending coronary artery (LAD) followed by 2 h reperfusion (R). Rats submitted to the MI-R protocol were administered bosentan at a dose of 3 mg/kg i.v. 20 min (BOS group) or saline (CON group) 20 min post-occlusion of LAD. After the 2 h reperfusion period the animals were euthanized and the heart rapidly excised. Cardiac tissue samples were snap frozen in liquid nitrogen for biochemical assay and were fixed in 10% formalin solution for histologic evaluation. Myocardial I-R resulted in a significant increase (p < 0.05) in the myocardial malondialdehyde levels and a decrease (p < 0.01) in the myocardial reduced glutathione content. These changes were associated with significant decreases in the myocardial activity of antioxidant enzymes superoxide dismutase (p < 0.05) and catalase (p < 0.01) and severe tissue damage in the jeopardized myocardium in the CON group as compared with the non-myocardial ischemia-reperfusion (NMI-R) SHAM group. Bosentan exerted marked tissue protective effect as assessed by histologic evaluation of the myocardium. The drug significantly (p < 0.05) attenuated myocardial oxidative stress and restored the cellular antioxidant defense mechanisms as compared with the saline-treated controls subjected to the MI-R protocol. Furthermore, bosentan also exerted a marked effect on peripheral hemodynamics and heart rate during the reperfusion phase (data reported elsewhere). These results are consistent with the concept that endothelin-1 may be involved in the pathogenesis of myocardial ischemia and infarction. This study demonstrates the antioxidant effect of non-selective endothelin receptor antagonism elucidating that, part of the aetiology of ischemia and reperfusion induced myocardial injury involves impaired antioxidant defenses.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bosentan
  • Cardiotonic Agents / pharmacology*
  • Catalase / analysis
  • Catalase / metabolism
  • Endothelin Receptor Antagonists*
  • Glutathione / analysis
  • Glutathione / metabolism
  • Male
  • Malondialdehyde / analysis
  • Malondialdehyde / metabolism
  • Myocardial Ischemia / metabolism*
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocardial Reperfusion Injury / metabolism
  • Myocardium / chemistry
  • Myocardium / metabolism
  • Oxidative Stress / drug effects*
  • Rats
  • Rats, Wistar
  • Sulfonamides / pharmacology*
  • Superoxide Dismutase / analysis
  • Superoxide Dismutase / metabolism


  • Cardiotonic Agents
  • Endothelin Receptor Antagonists
  • Sulfonamides
  • Malondialdehyde
  • Catalase
  • Superoxide Dismutase
  • Glutathione
  • Bosentan